Huntingtin and the control of long distance transport of synaptic / extrasynaptic signals in health and disease

亨廷顿蛋白 (HTT) 是一种蛋白质，当突变时会导致亨廷顿病 (HD)，这是一种破坏性的神经系统疾病，它充当蛋白质复合物的支架，在轴突和树突中的囊泡和蛋白质运输中发挥着新兴作用。 HTT 与分子马达动力蛋白和驱动蛋白相互作用，调节运输的功效和方向性，将 HTT 置于功能节点的中心，调节轴突和树突中长距离信号的运输。在疾病的早期阶段，不存在结构损伤，而是存在突触功能损伤，表现为从突触到突触外 N-甲基-D-天冬氨酸受体 (NMDAR) 信号传导的转变。 Jacob 是一种突触核蛋白信使，可将 NMDAR 信号的突触或突触外起源编码并转导至细胞核，并在基因表达调节中发挥作用，导致细胞死亡或促进细胞存活和突触可塑性。 Jacob 的核运输需要沿着微管的主动输入蛋白和动力蛋白介导的逆行运输。多项研究提供了令人信服的证据，证明亨廷顿蛋白与参与基因转录、细胞信号传导和细胞内运输的蛋白质相互作用。最近的报告表明，亨廷顿蛋白可能提供一个将转录调节因子与分子马达连接起来的平台，以实现从突触到细胞核的运输。通过这个提案，我们将解决这个想法。我们还将研究基于微管的运输的扰动是否会导致 HD 中长距离信号传导的损伤。更具体地说，我们认为 HTT 和 Jacob 可以在整合从突触到细胞核的长程信号方面发挥重要作用，从而改变健康和 HD 中的基因表达。我们假设 Jacob（一种可以将 NMDAR 衍生信号体与核靶位点对接的蛋白质）与突变型 HTT 之间的功能相互作用可能会导致 HD 中的神经变性。我们将测试 HTT 和 Jacob 是否直接相互作用，我们的目标是确定在正常和 HD 条件下转运到细胞核的信号的分子身份，特别强调转录调节因子的非囊泡转运。最重要的是，我们想要评估突触外 NMDAR 是否会触发 HD 中 Jacob 的核输入以及这与细胞死亡和神经变性的关系。总而言之，拟议的工作计划将为 HTT 的生理功能提供新的认识，而这一点一直被忽视，同时我们将了解所研究的机制如何影响该疾病的病理生理学。

Huntingtin (HTT) the protein that when mutated causes Huntingtons disease (HD), a devastating neurological disorder acts as a scaffold for protein complexes with an emerging role in the transport of vesicles and proteins in axons and dendrites. HTT interacts with the molecular motors dynein and kinesin to regulate the efficacy and the directionality of transport placing HTT at the center of functional nodes that regulate the transport of signals over long distances in axons and dendrites. At an early stage of the disease no structural damage exists but rather an impairment of synaptic function that manifests in a shift from synaptic to extrasynaptic N-Methyl-D-Aspartate-receptor (NMDAR) signalling. Jacob is a synapto-nuclear protein messenger that encodes and transduces the synaptic or extra-synaptic origin of NMDAR signals to the nucleus and that plays a role in regulation of gene expression either leading to cell death or promoting cell survival and synaptic plasticity. Nuclear trafficking of Jacob requires an active importin- and dynein- mediated retrograde transport along microtubuli. Several studies have provided compelling evidence that huntingtin interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that huntingtin might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we will address this idea. We will also investigate whether perturbation of microtubule-based transport contributes to impairments in long-distance signalling in HD. More specifically we propose that HTT and Jacob could play a major role in integrating long-range signals from the synapse to the nucleus and consequently will modify gene expression in health and in HD. We assume that a functional interplay between Jacob, a protein that can dock an NMDAR-derived signalosome to nuclear target sites and mutant HTT might contribute to neurodegeneration in HD. We will test whether HTT and Jacob interact directly and we aim to determine the molecular identity of the signals transported to the nucleus in normal and HD conditions with special emphasis on non-vesicular transport of transcriptional regulators. Most important we want to assess whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. Taken together the proposed work program will shed new light on the physiological function of HTT, which has been neglected and at the same time we will learn how the investigated mechanisms impacts on the pathophysiology of the disease.